Asymmetric Synthesis of 2-Keto-1,3-diols and Protected 1,2,3-Triols Bearing Two Quaternary Stereocenters

Abstract

A s y m m e t r i c S y n t h e s i s o f 2 -K e t o -1 , 3 -d i o l s a n d P r o t e c t e d 1 , 2 , 3 -T r i o l s Abstract: The asymmetric synthesis of 1,3-dihydroxy-2-ketones bearing two quaternary stereocenters in a-and a¢-position starting from 2,2-dimethyl-1,3-dioxan-5-one-SAMP-hydrazone is described. The protocol involves four consecutive a/a¢-alkylations, the last one being carried out in the presence of DMPU as additive. After acidic cleavage of both the chiral auxiliary and the acetal function in a two-phase system, the title compounds are obtained with high stereoselectivity (de ≥ 91-97%, ee ≥ 96%) and in moderate to very good overall yields (14-61%). In addition, 1,2-quaternary 1,3-protected 1,2,3-triols were obtained by nucleophilic 1,2-addition to the carbonyl group as single stereoisomeres (de, ee ≥ 96%) in excellent yields.The tertiary alcohol moiety bearing a methyl group as one of its substituents can be found in a large number of polyoxygenated biologically active natural products. For instance, it is a characteristic structural feature in sugars such as L-mycarose 1 as part of the antibiotic erythromycin 2 or L-olivomycose 3 present in apoptolidin. 4 Furthermore it can be found in trachycladine A and B, which were isolated from the marine sponge Trachycladus laevispirulifer (Carter) and belong to the class of nucleosides with remarkable biological activity. 5 Also pheromones, for example sordidin, 6 the aggregation pheromone of the banana weevil Cosmopolites sordidus (Germar) or frontalin, 7 one of the aggregation pheromones of the southern pine beetle Dendroctonus frontalis, contain this tertiary alcohol subunit. In addition, it is a structural element in biologically active compounds such as staminol A, 8 neoilludin A and B 9 or anisatin 10 and citreoviral, 11 which proved to be potent neurotoxins. Convenient methods for the formation of quaternary stereocenters have been reviewed by Martin, 12 Fuji, 13 Corey, 14 Christoffers, 15 Overman, 16 and Yus et al. 17 The major routes to highly enantiomerically enriched tertiary alcohols are the 1,2-addition to prochiral ketones, 18 the Jacobsen epoxidation 19 of alkenes with subsequent cleavage or the Sharpless dihydroxylation 20 of trisubstituted alkenes.Recently we reported on the asymmetric synthesis of protected 2-keto-1,3-diols and 1,2,3-triol building blocks bearing one quaternary stereogenic center starting from easily available 2,2-dimethyl-1,3-dioxan-5-one 21 employing the SAMP/RAMP-hydrazone methodology. 22,23 We have now extended this highly stereoselective alkylation technique towards an efficient diastereo-and enantioselective synthesis of 1,3-diol derivatives bearing two quaternary centers in 1,3-or in 1,2-position, respectively.As depicted in Scheme 1 the asymmetric synthesis of the title a,a¢-quaternary 2-keto-1,3-diols 4 was achieved following our protocol of sequential a-alkylations of dioxanone-SAMP-hydrazone 1 24 and subsequent cleavage of both the chiral auxiliary and the acetal moiety.The dioxanone-SAMP-hydrazone (S)-1 was...

Asymmetric Synthesis of 4′-epi-Trachycladines A and B

“…11 Thus, our synthetic route started with 2,2-dimethyl-1,3dioxan-5-one employing the SAMP-/RAMP-hydrazone methodology. 10,12 As previously reported for the RAMPhydrazone of 7 the enantiomeric SAMP-hydrazone of 7 was alkylated twice with MeI at the aand a¢-positions. 13 Subsequent a-alkylation with benzyloxymethyl chloride (BOMCl) afforded the trisubstituted hydrazone 8 in very good overall yield (68% over 4 steps), and excellent diastereo-and enantiomeric excesses (de, ee ≥ 96%).…”

N,N-Dialkylhydrazones in Organic Synthesis. From Simple N,N-Dimethylhydrazones to Supported Chiral Auxiliaries

“…The ultimate extension of the alkylation methodology toward the assembly of two quaternary α-carbon atoms of a hydrazone has been demonstrated in the asymmetric synthesis of 1,3-dihydroxy-2-ketones 131 (Scheme ). The ketones, bearing two quaternary stereocenters in the α- and α′-positions, were made starting from 2,2-dimethyl-1,3-dioxan-5-one SAMP-hydrazone ( 77 ) by four consecutive α- and α′-lithiation/alkylation procedures.…”

“…The low yields were attributed to the high steric hindrance caused by the two quaternary carbon atoms. Acidic cleavage of 130 with 6 M aqueous HCl/pentane in a two-phase system (typically requiring a few days) removed both the chiral auxiliary and the acetal function (acetonide protection), providing 1,3-dihydroxy-2-ketones 131 in moderate to very good overall yields (14−61%) and with high stereomeric purity (de ≥ 91−97%, ee ≥ 96%) …”